DE3317000A1 - 4-OXO-THIAZOLIDIN-2-YLIDEN-ACETAMIDE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THE USE THEREOF FOR THE CONTROL OF DISEASES OF THE CENTRAL VENTILATION SYSTEM - Google Patents

Abstract

4-Oxothiazolidin-2-ylidene-acetamide derivatives, processes for their preparation, pharmaceutical compositions and a method for treating diseases of the central nervous system such as epilepsy are described.

Description

R is a hydrogen atom, a saturated or unsaturated straight-chain or branched aliphatic hydrocarbon rest with up to 4 carbon atoms, one

Aryl or aralkyl group, R is a hydrogen atom or a straight-chain or branched alkyl radical with up to 3 carbon atoms, X a hyphen or a straight-chain or branched alkylene chain with up to 4

3 4 5 carbon atoms and the radicals R, R and R, which are the same or can be different, a hydrogen atom, a straight-chain or branched alkyl radical with up to 4 carbon atoms, a straight-chain or branched alkoxy group with up to 4 carbon atoms, where two adjacent radicals together also have a methylenedioxy- or can form ethylenedioxy, a halogenator, a nitro group or a lower alkoxycarbonyl radical mean up to 5 carbon atoms.

.1. "* - 6 ■« ♦ ··

Compounds of the general formula I are preferred, in which R is a hydrogen atom, a saturated or unsaturated alkyl radical with 1 to 3 carbon

atoms, a phenyl or benzyl radical, R a hydrogen atom, a methyl or ethyl group, X a hyphen or a branched alkylene group with 1-3

3 4 5 carbon atoms and R, R and R, which may be the same or different, a hydrogen atom, a Mean methyl, ethyl, methoxy or ethoxy group, where two adjacent radicals together also a methylenedioxy group can form a fluorine, chlorine, bromine, iodine atom or a nitro group or a lower alkoxycarbonyl radical means with 1-3 carbon atoms.

Very particular preference is given to compounds of the general formula I in which R is a hydrogen atom,

2 is a methyl, ethyl, allyl or benzyl radical, R a Hydrogen atom, a methyl radical, a hyphen

3 4 5 or an ethylidene group and R, R and R, which may be the same or different, a hydrogen atom, a Means methyl radical or a chlorine or bromine atom.

The invention also relates to a process for the preparation of compounds of the general formula I, characterized in that one either

a) a compound of the general formula II

(II), CH-COY

in which R has the abovementioned meaning and y represents a reactive group

in a manner known per se with a compound of the general formula (III)

(III),

2 3 4 5 in which the radicals R, R, R and R and X have the meaning given above,

reacted and optionally then N-alkylated or

b) a compound of the general formula IV

. O N = C-CH2-C-N-X

3 4 5 in which the radicals R, R and R and X die

have the above meaning
with a thioglycolic acid ester of the general formula V

HS-CH ₂ -COOR ⁶ (V),

■ in which R is a lower alkyl radical with up to Represents 5 carbon atoms,

converts the compounds obtained in general Formula VI

CH-CO-N-X

in which R ² , R ³ , R ⁴ and R ⁵ and X have the meaning given above,

if desired, then N-alkylated in a manner known per se and the compounds thus obtained of general formula I isolated in a manner known per se.

The compounds of general formula I are valuable medicaments with an unusually broad anticonvulsant effect Effect profile and excellent tolerance. They are particular for a comprehensive, anti-epileptic Therapy suitable.

The term epilepsy is a collective name for a class of chronic diseases of the central Nervous system, which is the occurrence of episodic seizures with abnormal motor ("convulsions"), sensory and psychological phenomena have in common.

The frequency of epilepsies is surprisingly high and is around 0.5% of the population. The wealth of forms the epilepsy forces to pharmacotherapy that due to the necessity of an often changing, differentiated treatment with different drugs gets complicated.

Anti-epileptic substances are of various types chemical classes. These include barbiturates, pyrimidones, hydantoins, oxazolidinediones, succinimides, Benzodiazepines, Iminostilbenes, and Valproates. According to their effects in laboratory models are representatives of these classes more or less for the therapy of partial (focal), generalized, temporal or myoclonal Suitable for seizures and absences. An ideal anti-epileptic would therefore be one substance, all of them Is able to suppress types of seizures and absences and does not produce any undesirable side effects.

A disadvantage of the known anti-epileptic drugs is that they often fail when attempting to control seizures and in addition cause CNS dysfunction and other side effects up to aplastic anemia (Goodman, Gilman, The Pharmacological Basis of Therapeutics - 6th Ed. 198o, pp. 451 ff). Even if known anticonvulsants are used in a suitable selection and combination, only 5o% seizures occurring in the treated patient can be brought under control. Even in the case of success, you have to however, unpleasant side effects are usually accepted.

The compounds of general formula I are not only distinguished by an extraordinary breadth their spectrum of action, but also through a high potency and extremely well tolerated. Although these findings were only supported by animal experiments the compounds of the invention are expected to make a significant advance in the process the treatment of epilepsy in its various forms mean.

The compounds of general formula I can due to the C-C double bond on the thiazolidine ring in one Z and Ε configurations occur. The present application includes both forms.

The starting compounds II and III are known or can be produced by known methods. Ver

1 bonds of the general formula II, in which R is a hydrogen atom, can be obtained starting from the known acids (R = H, Y = OH) by alkylation on the ring nitrogen after previous esterification using lower aliphatic alcohols and subsequent careful hydrolysis (Annalen 665 (1963) p. 15o ff).

The corresponding t-butyl esters (Y = tert-butoxy group) are used in a particularly advantageous manner.

The method a) is preferably carried out in an aprotic bipolar solvent, such as. B. dichloromethane, chloroform or dimethylformamide or in mixtures of such solvents.

As reactive groups come z. B. anhydrides, alkyl esters, mixed anhydrides, but especially the halides in question.

However, the reaction can also be carried out using alkyl esters (Y = lower alkoxy group).

The particularly reactive acid chlorides are produced by mixing the free acid (Y = OH) with a suitable acid halide, such as. B. thionyl chloride, oxalyl chloride or Pnosphorpentachlorid converts.

The compounds of general formula IV can be - starting from Cyanessxgsaureestern - such. B. ethyl cyanoacetate with corresponding aniline derivatives of the general formula VII

R ³

R ⁴

H ₂ N - <(-T) (VII),

3 4 5
in which R, R and R have the above meaning

to have

according to well known methods, e.g. B. by heating the reaction components with distillation of the Produce released ester alcohol.

The compounds of general formula I, in which Rl denotes a hydrogen atom are preferred produced by process b), since process a) gives unsatisfactory yields in individual cases.

The compounds I according to the invention can be applied enterally or parenterally in liquid or solid form be adorned. The main injection medium used is aqueous phases which contain the usual additives such as stabilizers and solubilizers contain. Solid carriers are z. B. starch, lactose, Mannitol, methyl cellulose, talc, highly dispersed silicic acids, higher molecular weight fatty acids (such as stearic acid) , Gelatine, agar-agar, calcium phosphate, magnesium stearate, animal and vegetable fats, solid high molecular weight polymers (such as polyethylene glycols); for Preparations suitable for oral administration can if desired Contain flavors and / or sweeteners. ■ The dosage of the compounds according to the invention is directed depending on the type and severity of the disease. The single oral dose is approximately 10–2oo mg.

The following examples serve to provide a more detailed explanation the invention:

example 1

(Z) - (4-Oxo-thiazolidin-2-ylidene) -Ivl- (2,6-dimethylphenyl) -acetamide

4.2 g (35 mmol) of ethyl thioglycolate are mixed with 6.6 g (35 mmol) of 2,6-dimethyl-anilide cyanoacetic acid and 0.13 g (1 mmol) of potassium carbonate. 15 ml of ethanol are then added and the mixture is heated to boiling for 3.5 hours while stirring. A further 15 ml of ethanol are then added and the mixture is cooled to 40.degree. The deposited precipitate is filtered off with suction, the crude product is recrystallized from 50% strength aqueous acetic acid, washed neutral with water and dried in vacuo. (Z) - (4-oxo-thiazolidin-2-ylidene) -N- (2,6-dimethylphenyl) acetamide is obtained; Mp. 25o ⁰ C (decomp.)

The 2,6-dimethylanilide cyanoacetic acid used as the starting material is made as follows:

11.3 g (0.1 mole) of cyanoacetic acid ethyl ester and 15.7 g (o, 13 mol) of 2,6-dimethylaniline are mixed and heated with stirring to 17O ⁰ C. The resulting ethanol is continuously distilled off; Here, the temperature rises up to 195 ⁰ C. The reaction has ended after 6 hours.

After cooling, the contents of the flask are recrystallized from 35o ml of ethanol. C., to yield the cyanoacetic acid 2,6-dimethylanilide in the form of colorless crystals of MP. 2O4 2O6 ⁰

Example 2

(Z) - (■ 3-Methyl-4-oxo-tliiazoliclin-2-ylueri) -n- (2,6-dimethylphenyl) acetamide

Option A

0.1 mol of (Z) - (3-methyl74-oxo-thiazolidin-2-ylidene) acetic acid are dissolved in a mixture of 500 ml of dichloromethane and 5 ml of dimethylformamide and to ml of thionyl chloride, dissolved in 3o ml of dichloromethane, within 45 Added dropwise at room temperature for minutes. The reaction mixture is allowed to stir at this temperature for a further 15 minutes and the now brown solution is evaporated in vacuo. The residue is dissolved in 500 ml of dichloromethane. In the filtered solution then is added dropwise within 3o minutes a solution of o, 2 moles of 2,6-dimethylaniline in 3o ml dichloromethane at room temperature and stirring is continued for 4 hours at 4o C. ⁰

The deposited precipitate is filtered off with suction and removed

5o% aqueous acetic acid recrystallized with water

washed neutral and. dried in vacuum.

(Z) - (3-: iethyl-4-oxo-thiazolidin-2-ylidene) -K- (2,6-dimethylphenyl) acetamide is obtained. Mp. 25o.4 ⁰ C (decomp.)

The (Z) - (3-methyl-4-oxothiazolidin-2-ylidene) acetic acid used as the starting product is made as follows:

2o g (Z) - (3-methyl-4-oxo-thiazolidin-2-ylidene) acetic acid t-butyl ester (Annalen 665 (1963) p. 15o ff) are dissolved in 45 ml of glacial acetic acid and at ⁰ ° C. with 8 ml of a 33% solution of hydrogen bromide in glacial acetic acid was added. After 15 minutes, ice water is added and the acid which has precipitated is filtered off with suction. Since the end product decomposes quickly, it is quickly crystallized from isopropanol. The free acid obtained can be used further immediately.

Variant B

ο, ο2ο mol (Z) - (4-oxo-thiazolidin-2-ylidene) -N- (2,6-dimethylphenyl) acetamide v / earth at room temperature in 22 ml of 1N sodium hydroxide solution with 2.3 g (o 0.024 mol) of dimethyl sulfate are added dropwise and the mixture is left to stir for a total of 1 hour. The methylation product is then extracted with dichloromethane and, after conventional work-up and crystallization from methanol, (Z) - (3-methyl-4-oxo-thiazolidin-2-ylidene) -N- (2,6-dimethy! Phenyl) acetamide from Mp. 25o.4 ⁰ C (dec.).

In a manner analogous to that described in Example 2, the following compounds are obtained:

b) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (2-chlorophenyl) acetamide; Mp. 193-194 ⁰ C (dec.). (Methanol)

c) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (3-chlorophenyl) acetamide. M.p. 275.3 ° C (dec.). (Dimethyl sulfoxide = DMSO)

d) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (4-chlorophenyl) acetamide; M.p. 295.5 ° C (dec.)

(DMSO-methanol)

e) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (2,3-dimethylphenyl) acetamide; Mp. 2o5 - 2o7 ⁰ C (decomp.) (Ethanol)

f) (+) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (1-phenylethyl ) aci

trolether).

nylethyl) acetamide; Mp 122 -. 125 ⁰ C (2-propanol / PE

g) (-) - (Z) - (3-I-lethyl-4-oxo-thiazolidin-2-ylidene) -N- (1-phenylethyl) acetamide; Mp. 55 - 6o C (dichloromethane)

h) (+) - (Z) - (3-methyl-4-oxo-thiazolidin-2-ylidene) -N- (1-phenylethyl) -acetamide; Mp. 65 - 7o ⁰ C (dichloromethane).

i) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -I \ I- (2-chloro-

6-methylphenyl) acetamide; Mp. 244 - 245 ⁰ C (ethanol).

j) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (2,6-dichlorophenyl) acetamide; Mp 224 -. 22-6 ⁰ C (toluene).

k) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (1,2,4,6 = trimethylphenyl) acetamide; M.p. 249.8 ° C (dec.) (Ethanol).

1) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (4-bromo-2,6-dimethylphenyl) acetamide; M.p. 263 C (methanol)

m) (Z) - (3-methyl-4-oxo-thiazolidin-2-ylidene) -N-methyl-N- (2-methylpheny1) acetamide; Mp. 114 - 115 ⁰ C (diisopropyl ether).

n) (Z) - (3-methyl-4-oxo-thiazolidin-2-ylidene) -K-methyl-W- (3-methylphenyl) acetamide; Mp 117 -. 110 ⁰ C (diisopropylether).

o) (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -W-methyl-N- (2,6-dimethylphenyl) acetamide; Mp. 153-154 C (diisopropyl ether).

p) (Z) - (3-Ethyl-4-oxo-thiazolidin-2-ylidene) -W- (2,6-dimethylphenyl) acetamide; Mp. 282.3 ⁰ C (dec.) (Propranol-2).

g), (Z) - (3-Allyl-4-oxo-thiazolidin-2-ylidene) -W- (2,6-dimethylphenyl) ace
nol 2 / water).

thy! phenyl) ac etarnide; Mp. 25o, 5 ⁰ C (decomp.), (Propa-

r) (Z) - (3-Benzyl-4-oxo-thiazoli'din-2-ylidene) -W- (2,6-dimethylphenyl) acetamide; Mp. 1-2-1.4 ° C. (Toluene).

Pharmacological comparative tests methodology

General

All substances were used as a vehicle in the convulsion tests 0.8% methocel mucus used. The premedication time was 30 minutes, unless otherwise stated, and the application took place i.g. in 20 ml / kg body weight.

Test animals were male mice (NMRI) with a body weight from 18 to 24 g, which under conditioned conditions were held. The feed was withdrawn 24 hours before the start of the experiment (unless otherwise stated), however, leave the drinking water until the start of the experiment.

In audiogenic convulsions, DBA / 2J mice became males Gender in the weight range of 5 - Io g used on the day before the attempt and not on an empty stomach was.

10 animals per dose were subjected to the test.

Phenytoin, valproate, GABA and Baclofen used.

Test models

1. Isoniazid spasm

Isonicotinic acid hydrazide (Isoniazid) was used as a convulsive at a dose of 25o mg / kg s.c. used, the observation time being 90 minutes.

2. Strychnine spasm

Strychnine was used as a convulsive nitric, cryst. in a Dose of 1.1 mg / kg s.c. applied, the observation time being 20 min p.a.

3. Electric shock

The HSE shock stimulator was used for the electric shock

Type 2o7 used.

Electrodes in

In the form of clip-on earrings attached to the ears of the mouse.

The duration of the shock was 0.3 s, the current intensity.

35 iuA (voltage self-regulating).

Phenytoin sodium (EPANÜTIn ( ^r )) was used as a positive standard at a dose of 50 mg / kg ig or sc.

The observation time was fixed at 5 minutes.

4. Pentetrazole spasm

14o mg / kg pentetrazole s.c. was used as a convulsive agent. applied. The observation time was 20 minutes.

5. Picrotoxin spasm

Picrotoxin was administered at a dose of 15 mg / kg s.c. administered. The animals were observed for 20 minutes.

6. Bicuculline spasm

The anticonvulsant was bicuculline purum. The dose was 3, ο mg / kg s.c. The observation time was 20 minutes.

7. Semicarbacid spasm

Semicarbacid hydrochloride was used as a crampon in a dose of 100 mg / kg s.c. used. The observation time was 90 min p.a. in each case.

8. 3-Hercaptopropionic acid

3-mercaptopropionic acid was diluted with physiological NaCl solution and adjusted to pH 7 with 6 mol / 1 NaOH and brought to the final volume with NaCl solution (10 ml / kg). The observation time was 30 minutes.

9. Audiogenic convulsions

The animals were tested with a 10.9 KHz tone from Ho dBÄ Sonicated for 30 seconds. The observation time was 1 min.

TABEL

COMPARISON NIX: INVESTIGATIONS OF THE ANTICONVULSIVE EFFECT IN THE CRAMP MODELS 1 - 9.

ED

so

ig, mouse ζ $)

O Q O

substance
example
No. ■ Electric
shock Pentetrazole
kranpf Semicarbacid
kranpf Picrotoxin
kranpf Strychnine
kranpf 3 MPA
cramp Isoniazid
kranpf Bicuculline
kranpf audiog.
cramps 2 a) 13.6 19.85. 14.06 11.30 14.88 8.7 5.32 2.68 2.9 5 2 i) 6.47 1.90 1.59 2.34 5.09 1.29 1.24 0.9 2 j) 4.03 1.80 3.41 1.52 5.68 1.73 5.0 0.8 Comparison =
substances - - / «■ 'J
J * ■> »
■ »* ·
M ■ »* Phenytoin 50
(ED 100)
12.5 (iv) 50
(ED 100) 50
(ED 90) > 200 inactive - 38 12.5 »» ■ ·
2,3,:.
* ♦
tr ι Valproate 200
(ED 40) about 250 100 inactive inactive 154 135 - * * * GABA inactive 500 60 inactive inactive - - - Baclofen ' 20th 100 4th 30th 8.5 20th 2.0 20th

') Side effects in all models

Acute toxicity and therapeutic index

The acute toxicity was determined on male mice (NMRI) with a body weight of 18-23 g. All test animals were fasted 20 hours before the start of the test. Water was available ad libitum. There were 4 animals in each dose group. The can sequence was logarithmic. The test substances were used as a suspension administered intragastrically in 0.88% methocel. The application volume was 20 ml / kg body weight. The animals were observed for a total of 7 days.

Table II

substance
Example no. ID 50
mg / kg ig (MausO) Therapeutic index
ID 50 / ED 50 *) 2 a) 1980 99.8-738.8 2 i) > 1600 > 243.3 - 1777.8 2 j). 1600 281.6-2000 Valproate 2000 8-14.8 GABA > 5000 > 10-80 Phenytoin 490 2.5-213 Baclofen 200 2-100

calculated for the largest and smallest ED _{5Q value}

Tables I and II show the superior spectrum of activity of the compounds on the one hand (Table I) and the extraordinary favorable relative safety due to the therapeutic quotients (Table II) on the other hand.

Claims (7)

Claim e R is a hydrogen atom, a saturated or unsaturated straight-chain or branched aliphatic Hydrocarbon radical with up to 4 carbon atoms men, an aryl or aralkyl group, R a hydrogen atom or a straight-chain or branched alkyl radical with up to 3 carbon atoms, X a hyphen or a straight or branched alkylene chain with up to 4 carbon atoms and the re- 3 4 5
ste R, R and R, which can be the same or different, a hydrogen atom, a straight-chain or branched alkyl radical with up to 4 carbon atoms, a straight-chain or branched alkoxy group with up to 4 carbon atoms, with two adjacent radicals together also a methylenedioxy or ethylenedioxy group can form a halogen atom, a nitro group or a lower alkoxycarbonyl radical with up to 5 Mean carbon atoms. 2. ^ Oxo-thiazolidine - ^ - ylidene acetamide derivatives according to claim 1, with v / elchen in the general formula I R a hydrogen atom, a saturated or unsaturated one Alkyl radical with 1 to 3 carbon atoms, a 2
Phenyl or benzyl radical, R a hydrogen atom, or a methyl or ethyl group, X a hyphen or a straight-chain or branched alkylene group with 1-3 3 4 5 Carbon atoms and R, R and R, which can be the same or different, a hydrogen atom, a methyl, Ethyl, methoxy or ethoxy group, where two adjacent radicals together also form a methylenedioxy group can, a fluorine, chlorine, bromine, iodine atom or a nitro group or a lower alkoxycarbonyl radical with 1-3 Means carbon atoms. 3. 4-Oxo-thiazolidin-2-ylidene-acetamide derivatives according to An. claim 1, in which in the general formula I R is a hydrogen atom, a methyl, ethyl, AlIyI- or benzyl radical, R a hydrogen atom or a methyl radical, X a hyphen or an ethylidene group 3 4 5 and R, R and R, which can be the same or different, represents a hydrogen atom, a methyl radical or a chlorine or bromine atom. 4. (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (2,6-dimethylphenyl) acetamide. 5. (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (2-chloro-6-methyl-phenyl) acetamide. 6. (Z) - (3-Methyl-4-oxo-thiazolidin-2-ylidene) -N- (2,6-dichlorophenyl) acetamide. 7. Process for the preparation of 4-oxo-thiazolidin-2-ylidene-acetamide derivatives according to claim 1 to 6, characterized in that inan either a) a compound of the general formula II (II), CH-COY in which R has the abovementioned meaning and y represents a reactive group. in a manner known per se with a compound of the general formula (III) R ³ (III) 2 3 4 5 in which the radicals R, R, R and R and X die have the above meaning reacted and optionally then W-alkylated or b) a compound of the general formula IV N = C-CH2-C-N-X 3 4 in which the radicals R, R and R and X have the meaning given above, with a thxoglycolic acid ester of the general formula V HS-CH.-COOR ⁶ (V), in which R is a lower alkyl radical with up to Represents 5 carbon atoms / converts the compounds of general formula VI obtained in v / which R ¹ , X, R, R and R have the meaning given above, if desired, then in a manner known per se ISf-alkylated and the compounds obtained in this way general formula I isolated in a manner known per se. Use of compounds according to Claims 1 to 6 in combating diseases of the central nervous system, especially epilepsy.